title: Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6.
abstract: Proinflammatory macrophages are key mediators in several pathologies; thus, controlling their activation is necessary. The endocannabinoid system is implicated in various inflammatory processes. Here we show that in macrophages, the newly characterized enzyme α/β-hydrolase domain 6 (ABHD6) controls 2-arachidonoylglycerol (2-AG) levels and thus its pharmacological effects. Furthermore, we characterize a unique pathway mediating the effects of 2-AG through its oxygenation by cyclooxygenase-2 to give rise to the anti-inflammatory prostaglandin D2-glycerol ester (PGD2-G). Pharmacological blockade of cyclooxygenase-2 or of prostaglandin D synthase prevented the effects of increasing 2-AG levels by ABHD6 inhibition in vitro, as well as the 2-AG-induced increase in PGD2-G levels. Together, our data demonstrate the physiological relevance of the interaction between the endocannabinoid and prostanoid systems. Moreover, we show that ABHD6 inhibition in vivo allows for fine-tuning of 2-AG levels in mice, therefore reducing lipopolysaccharide-induced inflammation, without the characteristic central side effects of strong increases in 2-AG levels obtained following monoacylglycerol lipase inhibition. In addition, administration of PGD2-G reduces lipopolysaccharide-induced inflammation in mice, thus confirming the biological relevance of this 2-AG metabolite. This points to ABHD6 as an interesting therapeutic target that should be relevant in treating inflammation-related conditions, and proposes PGD2-G as a bioactive lipid with potential anti-inflammatory properties in vivo.
authors.affiliation: Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Mireille
authors.initials: M
authors.lastname: Alhouayek
authors.forename: Julien
authors.initials: J
authors.lastname: Masquelier
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004952:Esters / Q000737:chemistry; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology; D005990:Glycerol / Q000737:chemistry; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004952:Esters; D005989:Glycerides; D053583:Interleukin-1beta; D054834:Lipocalins; D008070:Lipopolysaccharides; C584421:N-methyl-N-((3-(4-pyridinyl)phenyl)methyl)-4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester, carbamic acid; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2; C527261:ABHD6 protein, mouse; D008994:Monoacylglycerol Lipases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D005990:Glycerol; D015230:Prostaglandin D2
keywords: COX-2; FAAH; anandamide; glyceryl prostaglandin; prostaglandin synthase